Understanding arsenic carcinogenicity by the use of animal models

Although numerous epidemiological studies have indicated that human arsenic exposure is associated with increased incidences of bladder, liver, skin, and lung cancers, limited attempts have been made to understand mechanisms of carcinogenicity using animal models. Dimethylarsinic acid (DMA), an organic arsenic compound, is a major metabolite of ingested inorganic arsenics in mammals. Recent in vitro studies have proven DMA to be a potent clastogenic agent, capable of inducing DNA damage including double strand breaks and cross-link formation. In our attempts to clarify DMA carcinogenicity, we have recently shown carcinogenic effects of DMA and its related metabolites using various experimental protocols in rats and mice: (1) a multi-organ promotion bioassay in rats; (2) a two-stage promotion bioassay by DMA of rat urinary bladder and liver carcinogenesis; (3) a 2-year carcinogenicity test of DMA in rats; (4) studies on the effects of DMA on lung carcinogenesis in rats; (5) promotion of skin carcinogenesis by DMA in keratin (K6)/ornithine decarboxylase (ODC) transgenic mice; (6) carcinogenicity of DMA in p53(+/-) knockout and Mmh/8-OXOG-DNA glycolase (OGG1) mutant mice; (7) promoting effects of DMA and related organic arsenicals in rat liver; (8) promoting effects of DMA and related organic arsenicals in a rat multi-organ carcinogenesis test; and (9) 2-year carcinogenicity tests of monomethylarsonic acid (MMA) and trimethylarsine oxide (TMAO) in rats. The results revealed that the adverse effects of arsenic occurred either by promoting and initiating carcinogenesis. These data, as covered in the present review, suggest that several mechanisms may be involved in arsenic carcinogenesis. (C) 2004 Elsevier Inc. All rights reserved.

尽管大量流行病学研究表明，人类砷暴露与膀胱癌、肝癌、皮肤癌和肺癌发病率的增加有关，但利用动物模型了解致癌机制的尝试却很有限。二甲基胂酸（DMA）是一种有机砷化合物，是哺乳动物摄入无机砷后的主要代谢产物。近期的体外研究已证明DMA是一种强效的诱裂剂，能够诱导DNA损伤，包括双链断裂和交联形成。在我们试图阐明DMA致癌性的过程中，我们最近通过在大鼠和小鼠中采用各种实验方案展示了DMA及其相关代谢产物的致癌作用：（1）大鼠的多器官促进生物测定；（2）DMA对大鼠膀胱癌和肝癌发生的两阶段促进生物测定；（3）大鼠中DMA的2年致癌性试验；（4）DMA对大鼠肺癌发生影响的研究；（5）DMA在角蛋白（K6）/鸟氨酸脱羧酶（ODC）转基因小鼠中对皮肤癌发生的促进作用；（6）DMA在p53（+/-）基因敲除和Mmh/8 - 氧鸟嘌呤DNA糖基化酶（OGG1）突变小鼠中的致癌性；（7）DMA及相关有机砷化物在大鼠肝脏中的促进作用；（8）DMA及相关有机砷化物在大鼠多器官致癌试验中的促进作用；以及（9）大鼠中一甲基胂酸（MMA）和三甲基氧化胂（TMAO）的2年致癌性试验。结果显示，砷的不良影响要么是通过促进和引发致癌作用而产生的。本综述所涵盖的这些数据表明，砷致癌可能涉及多种机制。（C）2004爱思唯尔公司。保留所有权利。